Alteration of prostaglandin I2 on ripening in rabbit uterine cervix

We have attempted to clarify the relationship between PG synthesis and ripening in rabbit uterine cervix. In this paper, I examined whether PGI2 release from endogenous arachidonic acid is changed in ripening in the uterine cervix. The release of 6-keto PGF1 alpha significantly increased after the 20th day of gestation and at term reached its maximum, which was about six times that of non-pregnant rabbits. I then measured the activity of phospholipase A2 in the tissue and found that it was significantly increased during gestation. Furthermore, to determine which cells synthesize PGI2, several kinds of cells from the uterine cervix of non-pregnant and pregnant rabbits were isolated and cultured. Among these cells, smooth muscle cells were shown to have the PGI2 synthesizing activity. The rate of conversion of arachidonic acid to PGI2 in the cell was about 30%, and that to PGE2 was negligible. To examine the change in PGI2 synthesis with gestational age, cells from both non-pregnant and from the 25th day of gestation were cultured and the release of PGI2 from these cells was determined by radioimmunoassay of 6-keto PGF1 alpha. The release of 6-keto PGF1 alpha in gestation was about three times as high as in the cells from non-pregnant rabbits.     

Effects of dexamethasone on the uterine and umbilical vascular beds during basal and hypoxemic conditions in sheep

OBJECTIVE: The purpose of the study was to test the hypotheses that maternal treatment with dexamethasone leads to a reduction in basal umbilical blood flow and diminishes the fetal umbilical hemodynamic response to acute hypoxemic stress in sheep. STUDY DESIGN: While under general anesthesia, 23 ewes and their fetuses were instrumented with vascular catheters and transonic blood flow probes around a uterine and umbilical artery at 117 days of gestation (term, approximately 145 days). At 124 days, the ewes were injected intramuscularly with 2 doses of either dexamethasone (12 mg) or saline solution at 24-hour intervals. All animals experienced 2 episodes of hypoxemia during treatment (125+/-1 days) and after treatment (128+/-1 days). RESULTS: Maternal dexamethasone treatment caused a sustained increase in fetal arterial blood pressure (from 41+/-3 mm Hg to 45+/-3 mm Hg) and a transient fall in umbilical vascular conductance (from 6.2+/-0.9 mL. min(-1). [mm Hg](-1) to 5.4+/-0.7 mL. min(-1). [mm Hg](-1)). During both episodes of hypoxemia, there was a significant increase in umbilical blood flow in the controls, but not in the dexamethasone-treated animals. CONCLUSION: Maternal dexamethasone treatment with doses used in human clinical practice significantly decreased basal umbilical vascular conductance and prevented the normal increase in umbilical blood flow that is induced by acute hypoxemia in fetal sheep.     

Cigarette smoking and pregnancy I: ovarian, uterine and placental effects.

This review examines the major observations and principal controversies relating to the effects of smoking and the constituents of tobacco on ovarian, uterine and placental tissues. Maternal exposure is assessed relative to specific tobacco-related chemicals and the feto-placental impact of mutagenic products, in addition to nicotine replacement as a pharmacological intervention for smoking cessation. Important new information is being learned from clinical in vitro fertilization and assisted reproduction technologies regarding the effects of smoking on fertility. Present evidence supports an adverse effect of smoking on ovarian function which is prolonged and dose-dependent, whereas there appear to be more reversible effects on implantation and ongoing pregnancy. The anti-oestrogenic effect of smoking is reviewed in terms of direct effects of nicotine, cadmium and polyaromatic hydrocarbons on oestrogen synthesis and metabolism, oocytes and granulosa-luteal function. Innovative new models provide evidence that smoking may alter fertility through effects on uterine-fallopian tube functions which mediate gamete and conceptus transport. It is of interest that smoking is associated with a decreased incidence of uterine fibroids, endometriosis and uterine cancer, which may reflect inhibitory effects of smoke constituents on uterine cell proliferation and extracellular matrix interactions. The increased miscarriage rate among mothers who smoke may be related to direct adverse effects of nicotine, cadmium and polyaromatic hydrocarbons on trophoblast invasion and proliferation. In this respect, alterations in trophoblast differentiation along invasive or proliferative pathways may explain the changes in endocrine function and vascular morphology that are observed in smokers. In summary, significant advances are being made in the understanding of cellular and molecular mechanisms which underlie the differential effects of cigarette smoking on reproductive tissues.     

The placental and fetal response to the intra-amniotic injection of prostaglandin F2alpha in midtrimester abortions.

The placental and fetal response to the intra-amniotic injection of prostaglandin F2alpha (PGF2alpha) for midtrimester abortions was evaluated. Maternal blood samples for radioimmunological determinations of serum progesterone, human placental lactogen (HPL) and alpha-fetoprotein (AFP) were taken before and serially until 24 hours after the injection of 40 mg (nine patients) or 75 mg (seven patients) of PGF2alpha. Fetal heart action was monitored ultrasonically during the same period. The average induction-abortion interval was 22-6 hours and was indepedent of the dose of PGF2alpha used. The mean progesterone and HPL levels showed a significant fall half an hour after PGF2alpha. The constant decreases began only at 5 hours and later. The mean AFP levels increased rapidly after 5 hours following injection of PGF2alpha. The feral heart stopped at a mean of 10-4 hours (range 0-5 to 25 hours) after the injection of PGF2alpha. No relationship between the time of fetal death or rises in AFP and the induction-abortion interval could be detected. The primary hormonal response of the placenta and the efficacy of exogenous PGF2alpha were not related, indicating the possibility that the abortifacient property of PGF2alpha is not related to its primary effect on placental hormone synthesis or release.     

Human placental oxytocin and its increase by prostaglandin E2 and F2 alpha

To investigate the physiological roles of human placental oxytocin (OT)-like substance, partial purification of human placental extract and placental tissue culture were carried out. 1. Both oxytocic immunoreaction in our own specific radioimmunoassay and bioaction on rat uterine contraction were observed in the larger (MW greater than or equal to 5,000) and the smaller molecular part (MW not equal to 1,000) in partially purified placental extracts by gel-filtration using Sephadex G-25. 2. Prostaglandin E2 and F2 alpha enhanced the immunoreactive OT in the cultured human term placental tissue at doses of 1-100 micrograms/ml. These findings are considered to be significant in basic studies of human placental OT-like substance.     

Maternal ovine placental vascular responses to adenosine

We have examined the effect of adenosine given via retrograde uterine artery catheter at 25 mg/min to nine chronically catheterized near-term sheep pretreated with angiotensin II, 5 micrograms/min, via the jugular vein. Blood flows were measured by the microsphere technique. Flows were measured at rest, after 10 minutes of angiotensin II infusion, and after 1.5 minute of adenosine infusion. Blood pressure increased with angiotensin II infusion from 101 +/- 2.63 to 130 +/- 4.33 mm Hg (p less than 0.05) and then remained unchanged with local adenosine infusion at 129 +/- 4.33 mm Hg (NS). Organ resistances were: Tissue Control Angiotensin II Adenosine Uterine resistance/gm 299 +/- 0.04 767 +/- 83 (p less than 0.05) 355 +/- 37.7 (p less than 0.05) Cotyledonary resistance/gm 37.9 +/- 4.83 48.1 +/- 4.93 (p less than 0.05) 50.10 +/- 5.27 (p less than 0.05) The experimental uterine tissue resistance increased with angiotensin II and showed vasodilation in response to adenosine. The cotyledonary resistance increased with angiotensin II infusion but showed no change in response to adenosine. The maternal-placental response was anomalous. Angiotensin II-induced maternal-placental vasoconstriction cannot be opposed by the exogenous administration of adenosine.     

Scintigraphic studies of uterine and placental growth and placental migration during pregnancy

Placental scintigraphy with 113mIn (Indium) combined with cervical marking with a shielded 57Co (Cobalt) radioactive source was used to study uterine and placental growth in human pregnancy and placental location and migration in a total of 176 patients. Uterine length measurements can be used for selecting growth retarded fetuses. There was an approximately constant ratio between placenta diameter and uterine length (0.68 +/- 0.03). When the placenta was located on the ventral uterine wall, low implantation occurred in 61%. The corresponding figure for low implantation when the placenta was located on the dorsal uterine wall was 30%. The difference was highly significant. Placental migration was studied in 20 patients. Significant migration occurred in 11 cases. The placental margin closest to the internal cervical os migrated outwards about 3 cm on average.     

Ovine placental vascular response to the local application of prostacyclin

Rankin et al. have shown that prostacyclin does not dilate the ovine placenta, yet Clark et al. have shown that retrograde infusion of prostacyclin dilates the uterine vasculature. To determine the effects of prostacyclin on the sheep placenta, the two groups have collaborated. In five chronically catheterized near-term sheep, blood flows were measured by the radioactive microsphere technique. Control blood flows were measured and prostacyclin infused into the retrograde uterine artery catheter at 10 micrograms/min. The blood flows were again measured, and the area served by the catheter was then delineated by the injection of a green dye at the time of maternal euthanasia. The placenta and cotyledons were separated and the kidneys were obtained for assay. The systemic effects of prostacyclin were minimal and have been observed previously. The resistance of the myometrium fell from 566 +/- 99.9 to 322 +/- 63.9 mm Hg X ml-1 X min X gm (p less than 0.002). The placental tissue showed no change in resistance. When the tissues were combined, we observed a decrease in resistance from 0.38 +/- 0.18 to 0.32 +/- 0.14 mm Hg X ml-1 X min (p less than 0.004), thereby confirming the observation that there was indeed vasodilation downstream. However, the vasodilation was not in the placenta but in the myometrium, and we reconfirm our previous conclusion that prostacyclin does not dilate the sheep placenta.     

Effect of human menopausal gonadotrophin on the non-pregnant uterine response to intrauterine administration of prostaglandin E2

The effect of intrauterine instillation of 50 micrograms of prostaglandin E2 (PGE2) on the non-pregnant human uterus was evaluated in 10 volunteers, before and after systemic administration of human menopausal gonadotrophin (HMG). The cases were either in the early proliferative (n = 5) or late secretory (n = 5) phases of the cycle. Before HMG administration, the uterus responded to local PGE2 by stimulation in all the cases. After HMG treatment, no response to PGE2 was detected in eight cases and a decrease in uterine tonus was observed in two cases. The implications of these findings in certain physiological and pathological conditions relating to reproduction are discussed.     

Maturation of the uterine cervix by repeated intracervical instillation of prostaglandin E2

An attempt was made to ripen the uterine cervix in 100 high-risk pregnancy patients (pregnancy between 34 to 41 weeks' gestation), with the use of intracervical instillations of 0.25 mg of prostaglandin E2 mixed with a tylose gel. The maturation process was repeated every 48 hours. Forty-nine patients were delivered of infants after the first maturation and 51 patients required between two and nine instillations. In patients requiring multiple instillations, the mean delay between the first procedure and delivery was 9 +/- 4 days (range, 2.4 to 16 days). Among the 59 nulliparous women, only 23 were delivered of infants after a single maturation and 36 required multiple maturations (p less than 0.02). When the group of patients who were delivered of infants after a single maturation process was compared with the group requiring multiple maturations, no difference could be seen with regard to age, term of pregnancy, or Bishop cervical score at the time of inclusion in the study. The myometrial activity and the onset labor induced by prostaglandin E2, were similar in both groups. Fetal heart rate decelerations occurred in 16.3% (8/49) of the patients with single maturations and in 17.6% (9/51) of the patients who required multiple maturations. The outcome of the pregnancy and the rate of cesarean sections (24% and 27%) were similar in both groups. No patients required cesarean sections because of failed induction of labor. Cervical ripening after repeated applications of 0.25 mg of prostaglandin E2 seems to be safe for the fetus, providing that the patient is closely supervised.     

Coronary and uterine vascular responses to raloxifene in the sheep

OBJECTIVE: We sought to determine whether raloxifene increases coronary and uterine blood flow in ovariectomized ewes. STUDY DESIGN: Twelve ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, coronary blood flow, and uterine blood flow. Sheep received 17beta-estradiol, Estrace, raloxifene, or KY Jelly vehicle on separate days. RESULTS: 17beta-Estradiol increased uterine blood flow from 21 +/- 3 to 254 +/- 36 mL/min and coronary blood flow by 21% +/- 2% within 2 hours. Estrace increased uterine blood flow from 30 +/- 7 to 260 +/- 62 mL/min and coronary blood flow by 8% +/- 4% within 3 hours. Raloxifene increased uterine blood flow from 20 +/- 3 mL/min to 220 +/- 53 mL/min by 6 hours and coronary blood flow by 22% +/- 5% within 24 hours. To determine whether hemodynamic responses were mediated by nitric oxide, L -nitroarginine methyl ester was administered and produced an approximate 50% decrease in uterine blood flow for all 3 compounds. L -Nitroarginine methyl ester attenuated increases in coronary blood flow induced by 17beta-estradiol, Estrace, and raloxifene. CONCLUSION: Raloxifene has significant coronary and uterine vascular effects in the ovariectomized ewe. The coronary and uterine responses are partially mediated by nitric oxide.     

Temporal and regional regulation of major histocompatibility complex class I expression at the bovine uterine/placental interface

In most mammals trophoblast cells do not express major histocompatibility complex (MHC) antigens. This probably protects the placenta from immune attack. We have used immunohistochemistry to study the ontogeny of MHC class I expression by bovine trophoblast and endometrial epithelial cells. The interplacentomal, placentomal arcade and placentomal villous/crypt regions were studied. In the interplacentomal region a substantial proportion of trophoblast cells were class I positive from the sixth month on and about half of the endometrial epithelium was class I positive throughout pregnancy. In the arcade region trophoblast class I expression was first observed in the sixth month, increased slowly and peaked at term. Here there was no endometrial epithelial class I expression until term and then only a small percentage of cells were positive. In contrast, in the placentomal villous/crypt region both trophoblast and endometrial epithelium were class I negative throughout gestation. This study shows that cattle have extensive trophoblast class I expression. Moreover class I expression on placentomal, cryptal endometrial epithelium is shut down. Because binucleate trophoblast cells migrate and fuse with endometrial epithelial cells, total shut down of class I expression in areas of intimate interdigitation may be critical for avoidance of immunological rejection.     

Dexamethasone inhibits basal and stimulated prostaglandin E2 output from human placental cells by inhibition of prostaglandin H synthase.

In view of the temporal relation between elevated concentrations of glucocorticoids and prostaglandins (PG) at the time of parturition, we have examined the effects of dexamethasone on PGE2 output by mixed cell preparations from human placentae at term maintained in short-term (48 or 96 h) culture. Dexamethasone inhibited placental PGE2 output in a dose-dependent fashion. The effect on placental cells was more marked than on short-term cultures of amnion cells and was not influenced by the presence of progesterone. Dexamethasone also inhibited stimulated PGE2 output after addition of arachidonic acid. These results suggest that glucocorticoids inhibit placental PG output by a mechanism involving attenuation of PG synthase activity or expression and do not support a direct causal role for elevated maternal or fetal glucocorticoids at term on increased placental PG biosynthesis.     

Life-threatening hemorrhage due to uterine vascular abnormality

A case is reported of a 25-year-old woman stricken with prolonged and life-threatening menorrhagia from abnormal uterine vessels resembling hemangioma cavernosum. The condition was suspected at ultrasonic investigation. Hysterectomy was performed as an emergency operation.     

Use of prostaglandin F 2-alpha in placental period (author's transl)]

Reported in this paper is the intravenous application of prostaglandin F 2-alpha in the placental period and in cases of severe postpartum haemorrhage. -- Intravenous infusion of per-minute amounts between 40 and 80 micrograms in cases of atonic haemorrhage or between 30 and 45 micrograms in the placental period, in general, produced uterine contraction and clearly reduced blood loss.